Abstract Duchenne muscular dystrophy (DMD) is a devastating and universally fatal X-linked recessive disease of progressive striated muscle deterioration. DMD boys have severe skeletal muscle wasting early in life and they are typically wheelchair bound by age 10-12. DMD is fatal by the late teens to mid-twenties due to cardiac muscle and respiratory muscle failure. These grim realities underscore the tremendous urgency to discover and implement new approaches and therapies that could impact disease progression and outcomes in DMD. Significance of this proposal to the NIH is tremendous. There is no cure for DMD, or any effective clinical treatment that can halt or reverse the disease. This application derives outstanding health significance and impact by focusing on first-in-class synthetic membrane stabilizers that directly target the primary physiological defect in DMD: severe muscle membrane instability. Membrane stabilizers confer marked protection to dystrophic cardiac muscle, however, until now, dystrophic skeletal muscles were not significantly protected, tempering enthusiasm in the DMD field for this class of therapy. Now, for the first time to our knowledge, we find that pharmacodynamically optimized membrane stabilizers have a dramatic protective effect in dystrophic limb skeletal muscles in vivo. This potential therapeutic breakthrough has great significance to the NIH as a new viable approach to treat dystrophic striated muscles. The overarching hypothesis directing this proposal is that mechanistically guided structure-function analysis of synthetic block copolymers will illuminate new fundamental insights into the cellular basis of how membrane stabilization protect muscles. These mechanistically guided studies have great potential impact as they serve the required foundation in seeking the ultimate goal of effective long-term protection to dystrophic striated muscles in vivo.